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CXC Chemokine Ligand 13 and CC Chemokine Ligand 19 Cooperatively Render Resistance to Apoptosis in B Cell Lineage Acute and Chronic Lymphocytic Leukemia CD23⁺CD5⁺ B Cells¹

Hu Chunsong^2,*,, He Yuling^2,, Wang Li^2,, Xiong Jie^,, Zhou Gang, Zhang Qiuping, Gao Qingping, Zhang Kejian, Qiao Li^,¶, Alfred E. Chang^¶, Jin Youxin and Tan Jinquan^3,*,

^* Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China; Department of Immunology, and Laboratory of Allergy and Clinical Immunology, Institute of Allergy and Immune-Related Diseases and Center for Medical Research, Wuhan University School of Medicine, Wuhan, China; The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, China; Department of Hematology, The Renmin and Zongnan University Hospital, Wuhan University, Wuhan, China; and ^¶ Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109

CXCL13/CXCR5 and CCL19/CCR7 play a quite important role in normal physiological conditions, but the functions of both chemokine/receptor pairs in pathophysiological events are not well-investigated. We have investigated expression and functions of CXCL13/CXCR5 and CCL19/CCR7 in CD23⁺CD5⁺ and CD23⁺CD5^– B cells from cord blood (CB) and patients with B cell lineage acute or chronic lymphocytic leukemia (B-ALL or B-CLL). CXCR5 and CCR7 are selectively expressed on B-ALL, B-CLL, and CB CD23⁺CD5⁺ B cells at high frequency, but not on CD23⁺CD5^– B cells. Although no significant chemotactic responsiveness was observed, CXCL13 and CCL19 cooperatively induce significant resistance to TNF--mediated apoptosis in B-ALL and B-CLL CD23⁺CD5⁺ B cells, but not in the cells from CB. B-ALL and B-CLL CD23⁺CD5⁺ B cells express elevated levels of paternally expressed gene 10 (PEG10). CXCL13 and CCL19 together significantly up-regulate PEG10 expression in the same cells. We have found that CXCL13 and CCL19 together by means of activation of CXCR5 and CCR7 up-regulate PEG10 expression and function, subsequently stabilize caspase-3 and caspase-8 in B-ALL and B-CLL CD23⁺CD5⁺ B cells, and further rescue the cells from TNF--mediated apoptosis. Therefore, we suggest that normal lymphocytes, especially naive B and T cells, use CXCL13/CXCR5 and CCL19/CCR7 for migration, homing, maturation, and cell homeostasis as well as secondary lymphoid tissues organogenesis. In addition, certain malignant cells take advantages of CXCL13/CXCR5 and CCL19/CCR7 for infiltration, resistance to apoptosis, and inappropriate proliferation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Key Basic Research Program of China from the Ministry of Science and Technology of People’s Republic of China (Nos. 2001CB510004 and 2001CB510008), and by the National Natural Science Foundation of China (Nos. 39870674, 30572119, 30030130, and 30471509), Science Foundation of Anhui Province, China (No. 98436630), and Education and Research Foundation of Anhui Province, China (No. 98JL063) and Research Foundation from Health Department of Hubei Provincial Government, China (No. 301140344), and a special grant from the Personnel Department of Wuhan University, China. T.J. is a Chang Jiang Scholar supported by Chang Jiang Scholars Program from Ministry of Education, People’s Republic of China and Li Ka Shing Foundation, Hong Kong, People’s Republic of China.

² H.C., H.Y., and W.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Tan Jinquan, Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, 230032 Hefei, China or Department of Immunology, Wuhan University School of Medicine, Wuhan University, Dong Hu Road 115, 430071 Wuchang, Wuhan, People’s Republic of China. E-mail address: jinquan_tan{at}hotmail.com

⁴ Abbreviations used in this paper: CB, cord blood; B-CLL, B cell chronic lymphocytic leukemia; B-ALL, B cell lineage acute; ELC, EBV-induced gene-1 ligand chemokine; BCA, B cell-attracting chemokine; PEG10, paternally expressed gene 10; HCC, human hepatocellular carcinoma; PI, propidium iodide; IAP, inhibitor of apoptosis protein; MCNC, migrating cells on negative control; sh, short hairpin; PKC, protein kinase C; CI, chemotactic index; SIAH1, human homolog of Drosophila seven in absenia.

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